Pulsed Glucocorticoid Replacement Therapy

Cortisol (also called hydrocortisone) is a hormone produced by the adrenal glands that is essential for life. It is produced in a daily (circadian) rhythm with high levels first thing in the morning, falling to very low levels at night time. There are many medical conditions such as Addison's disease, congenital adrenal hyperplasia and pituitary disease where patients cannot produce enough of this hormone and therefore require replacement therapy. At present we give patients standard replacement therapy with tablets in an attempt to mimic a normal hormonal profile. However despite this their death rates remain twice that of the background population (similar to the increased risk from smoking) and patients often feel generally unwell with severe fatigue. It is now known that cortisol is released into the blood stream in approximately hourly pulses, and that this pattern of pulses is vital for the body's normal responses. Unfortunately this pulsatile pattern is not the pattern of replacement that we currently give patients and this could well contribute to the excess death rate and the poor quality of life of these patients. We propose to develop a tailor made treatment that allows us to deliver pulses of hydrocortisone under the skin in a way that closely mimics natural hormone release. We shall initially test this in normal healthy volunteers to ensure we provide infusion rates that are equivalent to those produced in a normal individual. Once we have established the best protocol for this, we will use this infusion pattern in patients with Addison's disease and congenital adrenal hyperplasia. We shall assess the effectiveness of the treatment by measuring their hormone levels and evaluating the improvement in their quality of life and emotional well being using psychological tests that are specifically tailored to the symptoms of our patients.

Glucocorticoid hormones secreted by the adrenal cortex are critical for life, and before steroid therapy was available patients with Addison's disease, congenital adrenal hyperplasia (CAH) and pituitary deficiency did not survive. However, despite the fact we now have available oral preparations of glucocorticoids and we administer these in a twice or three times daily regimen to try and mimic the normal circadian rhythm, our patients still have double the normal age related mortality and have major morbidity - predominately a feeling of generalised fatigue and lack of energy.
Underlying the classical circadian rhythm is a dynamic ultradian pulsatile pattern of cortisol secretion. This pattern is found in all mammalian species including man and is critical for normal gene regulation and for normal cognitive and metabolic function. It is now clear optimal regulation of glucocorticoid responsive genes absolutely requires pulsatile presentation of the ligand cortisol (in man) or corticosterone (in rodents). As we currently treat patients with constant as opposed to episodic receptor activation, we are inducing a very unphysiological regulation of both trans-activated and trans-repressed genes, which is likely to contribute both to the increased morbidity and mortality of our patients. We have developed a novel portable infusion pump that will deliver individually calculated pulsed subcutaneous hydrocortisone to more accurately mimic normal circadian and ultradian release. The aim of our proposed study is to validate this system in healthy volunteers and perform proof-of-concept studies in patients with Addison's and CAH. We shall examine the impact of our novel system upon biochemical parameters and assess the impact on psychological status using objective measurements of cognitive function, mood and tiredness as well as quality of life questionnaires.

Currently many patients on hydrocortisone replacement therapy feel so lethargic and lacking in energy that they cannot remain in employment and simply feel and behave chronically unwell. Furthermore, their markedly increased mortality reflects their poor metabolic, immunological and cognitive status. Over and above this, many patients are put on higher than replacement doses of glucocorticoids in the hope that this might diminish their symptoms - where as in fact it just increases their glucorticoid mediated side effects. Our proposed flexible physiological, pulsatile steroid replacement should radically improve basic management as indicated by biochemical testing (appropriate pre-awakening levels, low evening levels, adequate ACTH and 17 OHP suppression), better steroid replacement during inter-current illness (never missing a dose, better flexibility for temporarily increasing dosage), improved flexibility to match lifestyle (exercise, travel). In addition due to the ability to provide oscillatory levels of cortisol, this will lead to a more physiological effect on gene pulsing which may well be the link between Addison's and CAH and the increased rates of infectious and cardiovascular diseases and of cancer. A pulsatile replacement regimen should also improve pregnancy rates through accurate replacement rather than over replacement in both women (improvement in menses and management throughout the pregnancy) and men (optimal sperm quality and production). In our CAH patients, we would expect a very specific improvement in reproductive function, secondary to the reduction of excess androgen secretion as a result of our ability to reproduce the normal profile of early morning glucocorticoid pulses which will inhibit the exaggerated ACTH surge that occurs in the absence of normal physiological feedback. The physiological replacement will also decrease excess glucorticoid crossing the placenta and reduce long-term epigenetic consequences to the foetus. The technology we are developing will also have an impact on the treatment of inflammatory disease. We believe that our pump technological has the potential to place the NHS at the cutting edge of developing systems to treat asthmatics who have morning dips and rheumatoid arthritis patients who have morning stiffness - without the need for increasing steroid dosage and the related increase in steroid side effects. Indeed with the increasing realisation of the importance of timing of steroid dosage, there is considerable potential in using our technology for the treatment of many immune-mediated and malignant conditions.